The albumin-based drug delivery system is an effective drug delivery strategy for traditional chemotherapeutic drugs that can improve their antitumour efficacies and reduce systemic toxicities. The camptothecin derivative CPTS0001 has excellent antitumour activity in vitro, but it shows toxicity and side effects in vivo. In this study, we report the synthesis and biological evaluation of the β-glucuronidase-reactive albumin-binding prodrug Mal-glu-CPTS0001 based on quaternary ammonium. After intravenous administration, the compound covalently binds to plasma albumin through Michael addition, enabling it to accumulate in tumours, where tumour-associated β-glucuronidase triggers the selective release of CPTS0001. This prodrug significantly reduced the toxicity of the parent drug, and the maximum tolerated dose was increased by 2.5 times. At the same time, this prodrug enhanced the selectivity in vivo and improved the preferential accumulation of prodrug in tumours. Notably, this prodrug exhibited excellent in vivo antitumour effects in a murine breast cancer xenograft model without visible pathological toxicity.

基于白蛋白的给药系统是传统化疗药物的一种有效给药策略，可提高其抗肿瘤疗效并降低全身毒性。喜树碱衍生物CPTS0001在体外具有优异的抗肿瘤活性，但在体内表现出毒副作用。在这项研究中，我们报告了基于季铵的 β-葡萄糖醛酸酶反应性白蛋白结合前药Mal-glu-CPTS0001的合成和生物学评价。静脉内给药后，该化合物通过迈克尔加成与血浆白蛋白共价结合，使其在肿瘤中积累，肿瘤相关的 β-葡萄糖醛酸酶触发CPTS0001的选择性释放. 该前药显着降低了母体药物的毒性，最大耐受剂量增加了2.5倍。同时，该前药增强了体内选择性，提高了前药在肿瘤中的优先积累。值得注意的是，该前药在小鼠乳腺癌异种移植模型中表现出优异的体内抗肿瘤作用，且没有明显的病理毒性。